Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOA9232)

• DOT Name: Mitochondrial ornithine transporter 1 (SLC25A15)
• Synonyms: Solute carrier family 25 member 15
• Gene Name: SLC25A15
• Related Disease: Ornithine translocase deficiency
• UniProt ID: ORNT1_HUMAN
• Pfam ID: PF00153
• Sequence:
  MKSNPAIQAAIDLTAGAAGGTACVLTGQPFDTMKVKMQTFPDLYRGLTDCCLKTYSQVGF
  RGFYKGTSPALIANIAENSVLFMCYGFCQQVVRKVAGLDKQAKLSDLQNAAAGSFASAFA
  ALVLCPTELVKCRLQTMYEMETSGKIAKSQNTVWSVIKSILRKDGPLGFYHGLSSTLLRE
  VPGYFFFFGGYELSRSFFASGRSKDELGPVPLMLSGGVGGICLWLAVYPVDCIKSRIQVL
  SMSGKQAGFIRTFINVVKNEGITALYSGLKPTMIRAFPANGALFLAYEYSRKLMMNQLEA
  Y
• Function: Mitochondrial ornithine-citrulline antiporter (Probable). Catalyzes the exchange between cytosolic ornithine and mitochondrial citrulline plus an H(+), the proton compensates the positive charge of ornithine thus leading to an electroneutral transport. Plays a crucial role in the urea cycle, by connecting the cytosolic and the intramitochondrial reactions of the urea cycle (Probable). Lysine and arginine are also transported by the antiport mechanism (Probable). In addition, catalyzes an electroneutral exchange of ornithine or lysine for H(+), a reaction driven by the pH gradient across the inner membrane.
• Tissue Specificity: Highly expressed in liver, pancreas, testis, lung and small intestine. Lower levels are detected in spleen, kidney, brain and heart.
• Reactome Pathway: Urea cycle (R-HSA-70635)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ornithine translocase deficiency	DISITN7S	Definitive	Autosomal recessive	[1]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Mitochondrial ornithine transporter 1 (SLC25A15).	[2]

10 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mitochondrial ornithine transporter 1 (SLC25A15).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial ornithine transporter 1 (SLC25A15).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial ornithine transporter 1 (SLC25A15).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Mitochondrial ornithine transporter 1 (SLC25A15).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitochondrial ornithine transporter 1 (SLC25A15).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Mitochondrial ornithine transporter 1 (SLC25A15).	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Mitochondrial ornithine transporter 1 (SLC25A15).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mitochondrial ornithine transporter 1 (SLC25A15).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mitochondrial ornithine transporter 1 (SLC25A15).	[11]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Mitochondrial ornithine transporter 1 (SLC25A15).	[12]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [8] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [9] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.